The mitochondria are the primary oxygen consuming organelles of the cells of higher organisms, utilizing this oxygen consumption to provide the metabolic energy adenosine triphosphate (ATP) required for cell survival and growth. It is almost certainly the ability of the mitochondria to supply ATP which first fails when the cellular oxygen supply is inadequate, as the mitochondria combine their large oxygen requirement with a role as the principal source of cellular ATP. Thus, as the oxygen tension decreases to below that required by the maintenance of the mitochondrial ATP synthesis rate, the entire cellular metabolic balance is disturbed, while prolonged mitochondrial failure leads to irreversible cellular change. Our objective is to understand the regulation of cellular energy metabolism as it responds to stress in the form of: 1. Increased muscular activity such as in the perfused heart. 2. Increased ion transport such as in the stomach gastric mucosa. 3. Altered cellular (Pi). 4. Decreased cellular oxygen concentration (hyposia). A comprehensive model will be developed to permit quantitative description of the regulation of mitochondria oxidative phosphorylation and, in so far as possible, glycolysis. A variety of cellular systems including cultured cells and perfused organs will be subjected to the metabolic stress and changes in respiratory rate, glycolylic flux and metabolite levels will be measured. From these measurements it will be possible to identify regulatory sites and identify or infer the metabolite(s) responsible for activation or inhibition of these sites. Quantitative relationships, especially in hypoxia, will be determined for the metabolic regulation of mitochondrial respiration.